Polynucleotide kinase-phosphatase (PNKP) mutations and neurologic disease - PubMed (original) (raw)
Review
Polynucleotide kinase-phosphatase (PNKP) mutations and neurologic disease
Lavinia C Dumitrache et al. Mech Ageing Dev. 2017 Jan.
Abstract
A variety of human neurologic diseases are caused by inherited defects in DNA repair. In many cases, these syndromes almost exclusively impact the nervous system, underscoring the critical requirement for genome stability in this tissue. A striking example of this is defective enzymatic activity of polynucleotide kinase-phosphatase (PNKP), leading to microcephaly or neurodegeneration. Notably, the broad neural impact of mutations in PNKP can result in markedly different disease entities, even when the inherited mutation is the same. For example microcephaly with seizures (MCSZ) results from various hypomorphic PNKP mutations, as does ataxia with oculomotor apraxia 4 (AOA4). Thus, other contributing factors influence the neural phenotype when PNKP is disabled. Here we consider the role for PNKP in maintaining brain function and how perturbation in its activity can account for the varied pathology of neurodegeneration or microcephaly present in MCSZ and AOA4 respectively.
Keywords: Base excision repair; DNA damage signaling; DNA repair; Microcephaly; Neurodegeneration; Neurologic disease; Polynucleotide kinase phosphatase; Single strand break repair.
Copyright © 2016. Published by Elsevier B.V.
Figures
Figure 1. Disease-causing mutations in PNKP
The upper diagram shows the PNKP protein with the forkhead-associated domain (FHA), and the phosphatase and kinase domains indicated. The numbering indicates specific amino acid residues, and also the germline mutation changes found in PNKP in human syndromes. MCSZ mutations are listed in black, AOA4 mutations are purple and blue are mutations found in a compound heterozygote that showed an MCSZ phenotype. The P20S mutation in green is from an individual who manifest only seizures, but not neurodegeneration or microcephaly. The T424GfsX48 common mutation is present in homozygous individuals with MCSZ and also in siblings with both MCSZ, and in a compound heterozygous form in AOA4. The lower illustration indicates the effect of the T424GfsX48 change in the PNKP protein, showing premature termination in the kinase domain.
Similar articles
- The Phenotypic Spectrum of PNKP-Associated Disease and the Absence of Immunodeficiency and Cancer Predisposition in a Dutch Cohort.
Garrelfs MR, Takada S, Kamsteeg EJ, Pegge S, Mancini G, Engelen M, van de Warrenburg B, Rennings A, van Gaalen J, Peters I, Weemaes C, van der Burg M, Willemsen MA. Garrelfs MR, et al. Pediatr Neurol. 2020 Dec;113:26-32. doi: 10.1016/j.pediatrneurol.2020.07.014. Epub 2020 Jul 28. Pediatr Neurol. 2020. PMID: 32980744 - Pathological mutations in PNKP trigger defects in DNA single-strand break repair but not DNA double-strand break repair.
Kalasova I, Hailstone R, Bublitz J, Bogantes J, Hofmann W, Leal A, Hanzlikova H, Caldecott KW. Kalasova I, et al. Nucleic Acids Res. 2020 Jul 9;48(12):6672-6684. doi: 10.1093/nar/gkaa489. Nucleic Acids Res. 2020. PMID: 32504494 Free PMC article. - Impact of PNKP mutations associated with microcephaly, seizures and developmental delay on enzyme activity and DNA strand break repair.
Reynolds JJ, Walker AK, Gilmore EC, Walsh CA, Caldecott KW. Reynolds JJ, et al. Nucleic Acids Res. 2012 Aug;40(14):6608-19. doi: 10.1093/nar/gks318. Epub 2012 Apr 15. Nucleic Acids Res. 2012. PMID: 22508754 Free PMC article. - Neurological disorders associated with DNA strand-break processing enzymes.
Jiang B, Glover JN, Weinfeld M. Jiang B, et al. Mech Ageing Dev. 2017 Jan;161(Pt A):130-140. doi: 10.1016/j.mad.2016.07.009. Epub 2016 Jul 25. Mech Ageing Dev. 2017. PMID: 27470939 Free PMC article. Review. - Microcephalic primordial dwarfism in an Emirati patient with PNKP mutation.
Nair P, Hamzeh AR, Mohamed M, Saif F, Tawfiq N, El Halik M, Al-Ali MT, Bastaki F. Nair P, et al. Am J Med Genet A. 2016 Aug;170(8):2127-32. doi: 10.1002/ajmg.a.37766. Epub 2016 May 27. Am J Med Genet A. 2016. PMID: 27232581 Review.
Cited by
- A Specialized Reference Panel with Structural Variants Integration for Improving Genotype Imputation in Alzheimer's Disease and Related Dementias (ADRD).
Cheng PL, Wang H, Dombroski BA, Farrell JJ, Horng I, Chung T, Tosto G, Kunkle BW, Bush WS, Vardarajan B, Schellenberg GD, Lee WP. Cheng PL, et al. medRxiv [Preprint]. 2024 Jul 23:2024.07.22.24310827. doi: 10.1101/2024.07.22.24310827. medRxiv. 2024. PMID: 39108532 Free PMC article. Preprint. - Aberrant DNA repair reveals a vulnerability in histone H3.3-mutant brain tumors.
Giacomini G, Piquet S, Chevallier O, Dabin J, Bai SK, Kim B, Siddaway R, Raught B, Coyaud E, Shan CM, Reid RJD, Toda T, Rothstein R, Barra V, Wilhelm T, Hamadat S, Bertin C, Crane A, Dubois F, Forne I, Imhof A, Bandopadhayay P, Beroukhim R, Naim V, Jia S, Hawkins C, Rondinelli B, Polo SE. Giacomini G, et al. Nucleic Acids Res. 2024 Mar 21;52(5):2372-2388. doi: 10.1093/nar/gkad1257. Nucleic Acids Res. 2024. PMID: 38214234 Free PMC article. - DNA damage and repair: underlying mechanisms leading to microcephaly.
Ribeiro JH, Altinisik N, Rajan N, Verslegers M, Baatout S, Gopalakrishnan J, Quintens R. Ribeiro JH, et al. Front Cell Dev Biol. 2023 Oct 10;11:1268565. doi: 10.3389/fcell.2023.1268565. eCollection 2023. Front Cell Dev Biol. 2023. PMID: 37881689 Free PMC article. Review. - Ago2 and a miRNA reduce Topoisomerase 1 for enhancing DNA cleavage in antibody diversification by activation-induced cytidine deaminase.
Kobayashi M, Wakaguri H, Shimizu M, Higasa K, Matsuda F, Honjo T. Kobayashi M, et al. Proc Natl Acad Sci U S A. 2023 May 2;120(18):e2216918120. doi: 10.1073/pnas.2216918120. Epub 2023 Apr 24. Proc Natl Acad Sci U S A. 2023. PMID: 37094168 Free PMC article.
References
- Aguilera A, Garcia-Muse T. R loops: from transcription byproducts to threats to genome stability. Molecular cell. 2012;46:115–124. - PubMed
- Ahel I, Rass U, El-Khamisy SF, Katyal S, Clements PM, McKinnon PJ, Caldecott KW, West SC. The neurodegenerative disease protein aprataxin resolves abortive DNA ligation intermediates. Nature. 2006;443:713–716. - PubMed
- Al Tassan N, Khalil D, Shinwari J, Al Sharif L, Bavi P, Abduljaleel Z, Abu Dhaim N, Magrashi A, Bobis S, Ahmed H, Alahmed S, Bohlega S. A missense mutation in PIK3R5 gene in a family with ataxia and oculomotor apraxia. Hum Mutat. 2012;33:351–354. - PubMed
Publication types
MeSH terms
Substances
Supplementary concepts
Grants and funding
- R56 NS037956/NS/NINDS NIH HHS/United States
- P01 CA071907/CA/NCI NIH HHS/United States
- R01 NS037956/NS/NINDS NIH HHS/United States
- P30 CA021765/CA/NCI NIH HHS/United States
- P01 CA096832/CA/NCI NIH HHS/United States
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical